Sooty mangabeys are naturally infected with simian immunodeficiency virus (SIVsmm) subtypes that have identical genomic structure and similar nucleotide sequence as HIV-2. Sooty mangabeys suffer no adverse consequences of SIV infection while rhesus macaques develop simian immunodeficiency virus induced disease after experimental infection with viruses derived from sooty mangabeys. This project previously found that naturally infected sooty mangabeys have high plasma viral load and variable anti-SIV CTL responses suggesting that greater host containment of viral replication does not explain the lack of SIV-disease in mangabeys. During the last year, 3 rhesus macaques and 3 sooty mangabeys were experimentally infected with a common stock of SIVmac239/ON to identify characteristics of primary viremia that correlate with the virologic, immunologic, and clinical outcome of pathogenic and nonpathogenic SIV infection. All three mangabeys demonstrated attenuated viremia associate d with persistent strong anti-SIV CTL responses, while the three rhesus macaques had high levels of viremia, and CTL responses that diminished during clinical progression. The onset of anti-SIV CTL responses correlated temporally with the suppression of peak viremia in both primate host species. Attenuated viremia in these experimentally infected mangabeys, in contrast with naturally infected mangabeys which have high viremia, may be attributable to macaque adaptations of the virus stock used or some characteristic of natural infection that is not reproduced by intravenous challenge. Nevertheless, these experiments demonstrate that sooty mangabeys can acquire strong anti-SIV CTL responses in the setting of attenuated infection, arguing against congenital immune tolerance in mangabeys. Identification of the factors that determine the extent of immune tolerance early in the course of SIV infection in mangabeys may provide clues to how early therapeutic intervention could alter the n atural history of pathogenic viral infections.